Alzheimer's disease (AD) afflicts approximately 25 million people worldwide and is the most common cause of dementia in the elderly. There is an urgent need for new therapeutic target discovery and corresponding new compound development. A protein deposited in AD brains called amyloid- (A) has been hypothesized to play a critical role in AD pathogenesis. Ab can activate microglia to clear A but at the same time releasing cytotoxic substances to cause neuronal damage. Recently it was found that the voltage-gated potassium channel Kv1.3 (KCNA3) plays an important role in microglia activation. Therefore we intend to study if Kv1.3 plays a role in microglia activation, neurotoxicity, and amyloid deposition in AD. We found in our in vitro and in situ experiments that the selective Kv1.3 blocker PAP-1 blocked the neurotoxicity induced by A- activated microglia, but did not block the beneficial effect of microglia to phagocytose A. We also found strong Kv1.3 immunoreactivities in microglia associated with amyloid plaques in two AD mouse models. Our results suggest the involvement of Kv1.3 in microglia activation and neurotoxicity in AD. With the help of this grant we now wish to obtain in vivo proof of principle that Kv1.3 could be a therapeutic target and its specific inhibitors may have a therapeutic potential for AD. We will determine: 1. Do microglia activation and associated neuronal damage in response to pro-inflammatory stimuli in vivo require microglial Kv1.3 channel activity? To answer this question we will determine if blockade of Kv1.3 activity reduces microglial activation and dendritic degeneration in mice after treatment with lipopolysscharides or Ab oligomers. We will also examine the microglial Kv1.3 activity and its influence on the microglial activation state in response to these pro-inflammatory stimuli. 2. Can a selective Kv1.3 blocker called PAP-1 inhibit microglia activation in vivo and improve cognitive function of an AD mouse model called 3xTg-AD mice? To address this question, we will perform a therapeutic trial by treating 3xTg-AD mice with PAP-1 and determine the effect of PAP-1 on microglia activation state, amyloid deposition, tau pathology, and cognitive performance. Lay: Microglia, a type of white blood cells found in the brain, have been shown to contribute to the pathogenesis of Alzheimer's disease. The aims of our proposal are to test whether a potassium channel called Kv1.3 is important in microglia-caused damage. We will further test whether an inhibitor for Kv1.3 reduces microglia activity in an animal model of Alzheimer's disease.